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Compromised CDK1 activity sensitizes BRCA-proficient cancers to PARP inhibition

Nature Medicine volume 17, pages 875–882 (2011)Cite this article

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Abstract

Cells that are deficient in homologous recombination, such as those that lack functional breast cancer–associated 1 (BRCA1) or BRCA2, are hypersensitive to inhibition of poly(ADP-ribose) polymerase (PARP). However, BRCA-deficient tumors represent only a small fraction of adult cancers, which might restrict the therapeutic utility of PARP inhibitor monotherapy. Cyclin-dependent kinase 1 (Cdk1) phosphorylates BRCA1, and this is essential for efficient formation of BRCA1 foci. Here we show that depletion or inhibition of Cdk1 compromises the ability of cells to repair DNA by homologous recombination. Combined inhibition of Cdk1 and PARP in BRCA–wild-type cancer cells resulted in reduced colony formation, delayed growth of human tumor xenografts and tumor regression with prolonged survival in a mouse model of lung adenocarcinoma. Inhibition of Cdk1 did not sensitize nontransformed cells or tissues to inhibition of PARP. Because reduced Cdk1 activity impaired BRCA1 function and consequently, repair by homologous recombination, inhibition of Cdk1 represents a plausible strategy for expanding the utility of PARP inhibitors to BRCA-proficient cancers.

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Figure 1: Cdk1 depletion or inhibition reduces the formation of Rad51 foci and homologous recombination.
Figure 2: Cdk1 depletion results in reduced Rad51 foci, multiple chromosome aberrations, G2-M accumulation and cell death after PARP inhibition.
Figure 3: Cdk1-depleted or Cdk1-inhibited cells are highly sensitive to PARP inhibition.
Figure 4: Cdk1 depletion or inhibition protects nontransformed cells from PARP inhibitor treatment.
Figure 5: Cdk1 inhibition sensitizes cancer cells to inhibition of PARP in vivo.
Figure 6: Combined inhibition of Cdk1 and PARP causes tumor regression and prolongs survival in the KrasG12DTrp53L/L mutant lung cancer mouse model.

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Acknowledgements

This work was supported by US National Institutes of Health (NIH) Grants R01 CA090687 (G.I.S.), P50 CA089393 (Dana-Farber/Harvard Cancer Center (DF/HCC) Specialized Program of Research Excellence (SPORE) in Breast Cancer), including Developmental Project Funding (G.I.S.) and a Career Development Award (N.J.), as well as Susan G. Komen Post-Doctoral Fellowship Award KG080773 (N.J., G.I.S. and N.J.C.) and NIH Grant P50 CA090578 (DF/HCC SPORE in Lung Cancer) (G.I.S. and K.-K.W.). H.D.T., N.J.C. and D.R.N. were supported by a Programme Grant from Cancer Research U.K. K.-K.W. was also supported by a Uniting Against Lung Cancer grant and NIH grants U01 CA141576, R01 AG2400401, R01 CA122794, R01 CA140594 and 1RC2 CA147940-01. We thank M. Arora and J.D. Parvin for assistance with preliminary experiments; D. Skinner for technical assistance with tissue block and slide preparation; members of the Confocal and Light Microscopy Core Facility at the Dana-Farber Cancer Institute for technical assistance with acquisition of confocal microscopy images; M. Jasin (Memorial Sloan-Kettering Cancer Center) for U2OS pDR-GFP cells; and K. Hook, D. Madren and Z. Hostomsky of Pfizer for AG14361, AG014699 (PF-01367338) and AG024322 (PF-00176275).

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Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA

    Neil Johnson, Yu-Chen Li, Zandra E Walton, Katherine A Cheng, Danan Li, Kwok-Kin Wong & Geoffrey I Shapiro

  2. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Neil Johnson, Kwok-Kin Wong & Geoffrey I Shapiro

  3. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Scott J Rodig & Christine Unitt

  4. Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA

    Scott J Rodig, Christine Unitt & Roderick T Bronson

  5. Department of Radiation Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA

    Lisa A Moreau & Alan D D'Andrea

  6. Department of Pediatrics, Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Lisa A Moreau & Alan D D'Andrea

  7. Northern Institute for Cancer Research, University of Newcastle, Newcastle upon Tyne, UK

    Huw D Thomas, David R Newell & Nicola J Curtin

  8. Ludwig Center at Dana-Farber/Harvard Cancer Center, Boston, Massachusetts, USA

    Kwok-Kin Wong

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  1. Neil Johnson
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Contributions

N.J. and G.I.S. designed this study. N.J., Y-C.L., L.A.M., D.L., Z.E.W., K.A.C., C.U., R.T.B. and H.D.T. performed the experiments. N.J. and G.I.S. analyzed the data. N.J. and G.I.S. communicated with S.J.R., K.-K.W., D.R.N., A.D.d'A. and N.J.C. about the data interpretation and wrote the manuscript. G.I.S. supervised the project.

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Correspondence to Geoffrey I Shapiro.

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Johnson, N., Li, YC., Walton, Z. et al. Compromised CDK1 activity sensitizes BRCA-proficient cancers to PARP inhibition. Nat Med 17, 875–882 (2011). https://doi.org/10.1038/nm.2377

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